[unreadable] [unreadable] Project Summary - Research in microlymphatic circulation is exciting and rich in challenges as its importance in immune cell trafficking, cancer metastasis, and lipid metabolism are quickly becoming more appreciated and as its active biological roles in such processes are only now being discovered. Because of the complexity of this system, there is great need for new and quantitative tools and models to be developed and to use those new tools to explore these active roles in interdisciplinary manners. This proposal addresses the active role of lymphatics in lipid transport and metabolism, a topic which is very poorly understood and for which very few tools exist. The training stage of this grant will focus on two specific aims to lay the groundwork for future studies in lymphatic/lipid interactions: 1) to develop a tissue engineered model of the intestinal lymphatic microenvironment that recapitulates lipid transport functions and 2) to determine relative kinetics of nanoparticle transport across the tissue engineered construct of the intestinal microenvironment. The tissue engineered model of the intestinal microenvironment will be a useful tool for elucidating the biological mechanisms that control lymphatic function and as well as for providing feedback into the design and development of new oral drug delivery methods. Each of the aims will be continued during the independent research phase with the inclusion of in vivo studies to provide a more complete, relevant picture as to how lymphatics actively regulate lipid transport. These in vivo studies will focus on the role of lipids in the gut as well as provide a global picture as to how the lipid environment influences lymphatic pump function elsewhere in the body. [unreadable] [unreadable] Relevance - Despite the critical role of lymphatics in lipid transport in the intestine, almost nothing is known about how it is actively regulated or about the biology of lipid transport and metabolism by lymphatics. Some clinical correlations and experimental observations have linked the two, but this proposed research will establish foundational studies on how lymphatics actively affect lipid metabolism and will develop quantitative and relevant in vivo and in vitro tools for studying lipid trafficking and processing by the lymphatic endothelium as well as targeting lymphatics with drug delivery systems. This work will contribute to the eventual design of rational therapies to treat lymphedema, obesity, and other related disorders. [unreadable] [unreadable] [unreadable] [unreadable]